The ESX-4 substrates, EsxU and EsxT, modulate Mycobacterium abscessus fitness.

Lagune, M; Le Moigne, V; Johansen, MD; Vásquez Sotomayor, F; Daher, W; Petit, C; Cosentino, G; Paulowski, L; Gutsmann, T; Wilmanns, M; Maurer, FP; Herrmann, J-L; Girard-Misguich, F; Kremer, L

The ESX-4 substrates, EsxU and EsxT, modulate Mycobacterium abscessus fitness.

Lagune, M Le Moigne, V Johansen, MD Vásquez Sotomayor, F Daher, W Petit, C Cosentino, G Paulowski, L Gutsmann, T Wilmanns, M Maurer, FP Herrmann, J-L Girard-Misguich, F Kremer, L

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Publisher:: Public Library of Science (PLoS)
Publication Type:: Journal Article
Citation:: PLoS Pathogens, 2022, 18, (8), pp. 1-21
Issue Date:: 2022-08

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Field	Value	Language
dc.contributor.author	Lagune, M
dc.contributor.author	Le Moigne, V
dc.contributor.author	Johansen, MD
dc.contributor.author	Vásquez Sotomayor, F
dc.contributor.author	Daher, W
dc.contributor.author	Petit, C
dc.contributor.author	Cosentino, G
dc.contributor.author	Paulowski, L
dc.contributor.author	Gutsmann, T
dc.contributor.author	Wilmanns, M
dc.contributor.author	Maurer, FP
dc.contributor.author	Herrmann, J-L
dc.contributor.author	Girard-Misguich, F
dc.contributor.author	Kremer, L
dc.date.accessioned	2022-12-14T02:24:02Z
dc.date.available	2022-07-27
dc.date.available	2022-12-14T02:24:02Z
dc.date.issued	2022-08
dc.identifier.citation	PLoS Pathogens, 2022, 18, (8), pp. 1-21
dc.identifier.issn	1553-7366
dc.identifier.issn	1553-7374
dc.identifier.uri	http://hdl.handle.net/10453/164393
dc.description.abstract	ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT deletion mutant prevented phagosomal membrane disruption while maintaining M. abscessus in an unacidified phagosome. Unexpectedly, the esxUT deletion was associated with a hyper-virulent phenotype, characterised by increased bacterial loads and mortality in mouse and zebrafish infection models. Collectively, these results demonstrate that the presence of EsxU and EsxT dampens survival and persistence of M. abscessus during infection.
dc.format	Electronic-eCollection
dc.language	eng
dc.publisher	Public Library of Science (PLoS)
dc.relation.ispartof	PLoS Pathogens
dc.relation.isbasedon	10.1371/journal.ppat.1010771
dc.rights	Copyright: © 2022 Lagune et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credite
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0605 Microbiology, 1107 Immunology, 1108 Medical Microbiology
dc.subject.classification	Virology
dc.subject.mesh	Animals
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Mice
dc.subject.mesh	Mycobacterium
dc.subject.mesh	Mycobacterium abscessus
dc.subject.mesh	Mycobacterium marinum
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Type VII Secretion Systems
dc.subject.mesh	Zebrafish
dc.subject.mesh	Animals
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Mice
dc.subject.mesh	Mycobacterium
dc.subject.mesh	Mycobacterium abscessus
dc.subject.mesh	Mycobacterium marinum
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Type VII Secretion Systems
dc.subject.mesh	Zebrafish
dc.subject.mesh	Animals
dc.subject.mesh	Zebrafish
dc.subject.mesh	Mice
dc.subject.mesh	Mycobacterium
dc.subject.mesh	Mycobacterium marinum
dc.subject.mesh	Mycobacterium tuberculosis
dc.subject.mesh	Bacterial Proteins
dc.subject.mesh	Type VII Secretion Systems
dc.subject.mesh	Mycobacterium abscessus
dc.title	The ESX-4 substrates, EsxU and EsxT, modulate Mycobacterium abscessus fitness.
dc.type	Journal Article
utslib.citation.volume	18
utslib.location.activity	United States
utslib.for	0605 Microbiology
utslib.for	1107 Immunology
utslib.for	1108 Medical Microbiology
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Science
pubs.organisational-group	/University of Technology Sydney/Faculty of Science/School of Life Sciences
pubs.organisational-group	/University of Technology Sydney/Strength - CFI - Centre for Inflammation
utslib.copyright.status	open_access	*
pubs.consider-herdc	false
dc.date.updated	2022-12-14T02:23:49Z
pubs.issue	8
pubs.publication-status	Published
pubs.volume	18
utslib.citation.issue	8

Abstract:

ESX type VII secretion systems are complex secretion machineries spanning across the mycobacterial membrane and play an important role in pathogenicity, nutrient uptake and conjugation. We previously reported the role of ESX-4 in modulating Mycobacterium abscessus intracellular survival. The loss of EccB4 was associated with limited secretion of two effector proteins belonging to the WXG-100 family, EsxU and EsxT, and encoded by the esx-4 locus. This prompted us to investigate the function of M. abscessus EsxU and EsxT in vitro and in vivo. Herein, we show that EsxU and EsxT are substrates of ESX-4 and form a stable 1:1 heterodimer that permeabilizes artificial membranes. While expression of esxU and esxT was up-regulated in M. abscessus-infected macrophages, their absence in an esxUT deletion mutant prevented phagosomal membrane disruption while maintaining M. abscessus in an unacidified phagosome. Unexpectedly, the esxUT deletion was associated with a hyper-virulent phenotype, characterised by increased bacterial loads and mortality in mouse and zebrafish infection models. Collectively, these results demonstrate that the presence of EsxU and EsxT dampens survival and persistence of M. abscessus during infection.

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http://hdl.handle.net/10453/164393